-17.4-16.8 -16.8

-15.8

-17.8-18.4

-12.9-12.3

-13.8-14.6

-15.9-15.7

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Ch

ang

e in

SB

P (

mm

Hg

)

Omapatrilat Enalapril

HCTZHCTZ(n = 2476)(n = 2476)

Change in Systolic BP at Week 24 for Patients Receiving Change in Systolic BP at Week 24 for Patients Receiving Adjuncts After Week 8 (All Randomized Patients)Adjuncts After Week 8 (All Randomized Patients)

Other Other DiureticsDiuretics(n = 690)(n = 690)

AmlodipineAmlodipine(n = 695)(n = 695)

Other Other CCBCCB

(n = 735)(n = 735)ARBARB

(n = 274)(n = 274)

Beta Beta BlockersBlockers(n = 890)(n = 890)

OCTAVE (CV137-120)

-21.9

-13.2

-19.3

-9.5

-30

-25

-20

-15

-10

-5

0

OCTAVE Group 3: Effectiveness of OmapatrilatOCTAVE Group 3: Effectiveness of Omapatrilatin Patients Treated with HCTZ and Amlodipinein Patients Treated with HCTZ and Amlodipine

at Randomization at Week 24at Randomization at Week 24

SBP DBP

BP

Ch

ang

e (m

mH

g)

Omapatrilat (n = 65)Enalapril (n = 70)

OCTAVE (CV137-120)

Enalapril Comparison in Severe HypertensionEnalapril Comparison in Severe Hypertension(CV137-049) (CV137-049)

B71

Period ASingle-Blind PlaceboLead-In

Period CLong-TermOpen-Label

Period BDouble-Blind Randomized

SeDBP 115-130mmHg

40

B1 B15

A7

20 20 40

20

10

40 80

B8 B29

Level I Level II Level III Adjunct

Omapatrilat

Enalapril

B1 B71 C1

C1

Forced titrationto 40, elective to 80

Forced titration to 20, elective to 40

Efficacy Variable

OmapatrilatRegimen(n = 128)

EnalaprilRegimen(n = 57)

Trough SeDBP, mmHgBaseline Mean (sd)Adjusted Mean Change frombaseline (se)

Difference from Enalapril (95% CI)

118.3 (3.3)- 28.6 (0.8)

-2.2 (-4.9, 0.5)

118.3 (2.6)- 26.4 (1.1)

Trough SeSBP, mmHgBaseline Mean (sd)Adjusted Mean Change frombaseline (se)

Difference from Enalapril (95% CI)

176.2 (17.3) -37.4 (1.3)

-1.0 (-5.5, 3.6)

173.3 (15.4) -36.4 (1.9)

Trough Pulse Pressure, mmHgBaseline Mean (sd)Adjusted Mean Change frombaseline (se)

Difference from Enalapril (95% CI)

57.9 (16.5) -8.9 (1.0)

-1.1 (-2.5, 4.7)

55.0 (15.3) -10.0 (1.5)

CV137-049

Primary Efficacy ResultsPrimary Efficacy ResultsMean Changed from Baseline in Trough SeDBP,Mean Changed from Baseline in Trough SeDBP,

and SeSBP and SePP at Week 10and SeSBP and SePP at Week 10

(%) of Subjects

Primary TermOmapatrilat(N = 12,609)

Enalapril(N = 12,557)

Cough 8.7% 8.8%

Headache 7.4% 8.9%

Dizziness 6.8% 5.4%

Upper Respiratory Infection 6.8% 6.9%

Musculoskeletal Pain 5.2% 5.5%

Sinus Abnormality 3.2% 3.3%

Nausea / Vomiting 3.1% 3.0%

Fatigue 3.0% 3.0%

Tracheobronchitis 2.9% 2.8%

Flushing 2.3% 1.3%

Most Common Adverse EventsMost Common Adverse Events**

* Excluding Angioedema

OCTAVE (CV137-120)

OVERTURE TrialOVERTURE Trial

– Included all hospitalizations attributable to Included all hospitalizations attributable to heart failure as adjudicated by Endpoint heart failure as adjudicated by Endpoint Committee which required IV treatmentCommittee which required IV treatmentand had a duration and had a duration 24 hours 24 hours

SOLVD Treatment TrialSOLVD Treatment Trial

– Included all hospitalizations attributable to Included all hospitalizations attributable to heart failure by the investigator regardless heart failure by the investigator regardless of treatment or durationof treatment or duration

Definition of Hospitalization Definition of Hospitalization for Heart Failurefor Heart Failure

OVERTURE (CV137-068)

4 Wk4 Wk

Period BPeriod B

10 mg10 mg 40 mg40 mg 80 mg80 mgOmapatrilatOmapatrilat

3 Wk (max)3 Wk (max)

Period APeriod A

PlaceboPlacebo

ETTETT ETTETT

ETTETT ETTETT

RR

wk

2

wk

4

PlaceboPlacebo

Single blindSingle blind Double blindDouble blind

Day 28Day 28 Day 29Day 29

wk

1

BMS data on fileBMS data on file

+CAD+CAD+Exertional angina+Exertional angina

Study Design (CV137-071)Study Design (CV137-071)

BMS data on fileBMS data on file

Primary Efficacy Results:Primary Efficacy Results:Change in Peak Exercise Parameters vs Baseline ETTChange in Peak Exercise Parameters vs Baseline ETT

Omapatrilat Placebo

0

20

40

60

80

100

Time to OnsetTime to Onsetof Anginaof Angina

Maximal ExerciseMaximal ExerciseDuration Duration

Time to STTime to STDepressionDepression

p 0.001p 0.001p 0.001

Incr

ease

d T

ime

(sec

)

CV137-071

Diabetic Patients (CV137-046)Diabetic Patients (CV137-046)

Type II diabetics with microalbuminuria (30-300 mg/gram creatinine) or overt nephropathy ( 300 mg/gram creatinine)

2 week placebo lead-in

20 mg

2.5 mg

Randomization12 week

Double-blind

40 mg 80 mg

5 mg 10 mg

wk 4 wk 8

Elective titration

DBP 85-110 mmHg or SeSBP 130-180 mmHg

omapatrilat

amlodipine

Ad

just

ed G

M%

Ch

ang

e fr

om

Bas

elin

e

Omapatrilat Amlodipine

-30

-25

-20

-15

-10

-5

0

0 4 8 12

Study Week

Summary of Primary Efficacy ResultsSummary of Primary Efficacy Results

CV137-046

Adjusted Geometric Mean % Change from Baseline for Albumin Excretion Rate

omapatrilat

Wk 52(Echo)

Baseline EchoLVH

HypertensionDBP 95-115 mmHg

and / orSBP 160-200 mmHg

Force TitrationOpen-label adjuncts added to Level III

Wk 8 Wk 16 Wk 24(Echo)

20 mg 40 mg 80 mg + HCTZ 80 mg + HCTZ/AML

Losartan Comparison in LVH (CV137-038) Losartan Comparison in LVH (CV137-038)

50 mg 100 mg 100 mg + HCTZ 100 mg + HCTZ/AML

losartan

Summary of Primary Efficacy Results Summary of Primary Efficacy Results

CV137-038

Mean Changes from Baseline inEchocardiographic Measures at Week 24

Efficacy Variable

Omapatrilat 20/40/80 mg

(n = 158)

Losartan 50/100/100 mg

(n = 160)

LVMI, g/m² Baseline Mean (sd) Adjusted Mean Change (se) p-value

142.7 (29.7) -7.2 (1.7)

0.001

141.4 (28.5) -3.4 (1.7)

0.039

Difference from Losartan 95% CI p-value

-3.8 (-8.4, 0.9)

0.109

-- -- --

BP Changes From Baseline Per Study WeekBP Changes From Baseline Per Study Week

Adjunctive therapy %Adjunctive therapy %

OmapatrilatOmapatrilat 6.3 6.3 22.2 22.2 32.7 32.7 32.5 32.5 34.4 34.4

LosartanLosartan 16.5 16.5 50.0 50.0 54.8 54.8 59.3 59.3 60.0 60.0

00 2424 3030 3636 4444 5252WeekWeek

DBPDBP

SBPSBP

Ch

an

ge

in B

P (

mm

Hg

)C

ha

ng

e in

BP

(m

mH

g)

CV137-038CV137-038

0

-5

-10

-15

-20

-25

-30

-35

OmapatrilatOmapatrilat LosartanLosartan

CHOIRS BackgroundCHOIRS Background(Conduit Hemodynamics of(Conduit Hemodynamics of

Omapatrilat International Research Study)Omapatrilat International Research Study)

Elevated pulse pressure, an indirect measure Elevated pulse pressure, an indirect measure of increased vascular stiffness, associated with: of increased vascular stiffness, associated with:

– Myocardial infarction, strokeMyocardial infarction, stroke

– Development and progression of heart failureDevelopment and progression of heart failure

– Increased mortalityIncreased mortality

Current epidemic of uncontrolled systolic Current epidemic of uncontrolled systolic hypertension due to a lack of treatments thathypertension due to a lack of treatments thatreduce arterial stiffnessreduce arterial stiffness

Natriuretic peptides have a favorable effect on largeNatriuretic peptides have a favorable effect on largearteries in basic studies although their effects in arteries in basic studies although their effects in humans have not been elevatedhumans have not been elevated

CHOIRS: Study DesignCHOIRS: Study Design

Randomize: Force-titrationRandomize: Force-titrationWks 0, 2, 4Wks 0, 2, 4

Omapatrilat 10 / 40 / 80 mg daily(n = 104)

Enalapril 10 / 20 / 40 mg daily(n = 109)

8 Wks at maximal dose8 Wks at maximal dose

Trough (24 Hr)Trough (24 Hr)Hemodynamic StudyHemodynamic Study

(n = 80)(n = 80)

Trough (24 Hr)Trough (24 Hr)Hemodynamic StudyHemodynamic Study

(n = 87)(n = 87)

Withdrawn Withdrawn (n = 22)(n = 22)

Withdrawn Withdrawn (n = 24)(n = 24)

Baseline hemodynamic study (n = 213)Baseline hemodynamic study (n = 213)SBP SBP 160 mmHg 160 mmHg

EnalaprilOmapatrilat

Central and Peripheral Pulse PressureCentral and Peripheral Pulse Pressure

* = 0.005† = 0.05Mitchell, et al., Circulation 2002; 105:2955

*

Central Pulse Central Pulse PressurePressure

(80 (80 20 mmHg) 20 mmHg)

0

-5

-10

-15

-20

†

Brachial Pulse Brachial Pulse PressurePressure

(78.6 (78.6 16.6 mmHg) 16.6 mmHg)

0

-5

-10

-15

-20

†

Omapatrilat Target PopulationOmapatrilat Target Population

Patients with:Patients with:

A high risk of major cardiovascular events*A high risk of major cardiovascular events*

– Cardiovascular disease (e.g., MI, CHF)Cardiovascular disease (e.g., MI, CHF)

– Target organ damage (e.g., LVH, proteinuria)Target organ damage (e.g., LVH, proteinuria)

– 3 or more cardiovascular risk factors 3 or more cardiovascular risk factors

– Diabetes or renal diseaseDiabetes or renal disease andand

Hypertension that is difficult to controlHypertension that is difficult to controlwith existing medicationswith existing medications

*Based on WHO-ISH guidelines

Use with special caution in black patientsUse with special caution in black patientsand current smokersand current smokers

Subgroups at Increased CV Risk:Subgroups at Increased CV Risk:Change in Systolic BP at Week 24Change in Systolic BP at Week 24

Adjusted SBP Changeat Week 24 (mmHg)

Omapatrilat EnalaprilDifference(oma / ena)

-18.7-36.6

Severe Hypertension (n = 7197) Group 1 (n = 983)

-2.7-4.6

-17.6Diabetes Mellitus (n = 3275) -4.2

-20.7Atherosclerotic Disease* (n = 2283) -2.7

-22.2 ISH (n = 1332) -4.5

-17.0Renal Disease (n = 582) -3.6

-20.9Heart Failure (n = 233) -4.5

-15.9 -32.0

-13.4

-18.0

-17.7

-13.4

-16.4

*Includes chronic stable angina, unstable angina, myocardial infarction, and stroke / TIA OCTAVE (CV137-120)

Target Population – Baseline DemographicsTarget Population – Baseline Demographics (Diabetes, Renal Disease, Athero Disease, HF)(Diabetes, Renal Disease, Athero Disease, HF)

Omapatrilat

(n = 2849)

Enalapril

(n = 2840)

Age (Mean) 62 62

Age, n (%) 65 years

65 - 74 years 75 years

1654 (58%)

793 (28%)402 (14%)

1652 (59%)

802 (28%)385 (14%)

Gender, n (%)MaleFemale

1602 (56%)1247 (44%)

1566 (55%)1273 (45%)

WhiteBlack

2490 (87%)

314 (11%)

Race, n (%) 2488 (88%)

309 (11%)

OCTAVE (CV137-120)

OCTAVE: Efficacy in Target Population at Week 24 OCTAVE: Efficacy in Target Population at Week 24 (Diabetes, Renal Disease, Athero Disease, HF)(Diabetes, Renal Disease, Athero Disease, HF)

Change in Systolic BPChange in Systolic BPUse of NewUse of New

Adjunctive TherapyAdjunctive Therapy

-18.7

-15.0

-30

-25

-20

-15

-10

-5

0

24

30

0

5

10

15

20

25

30

35

40

45

50

-3.6**-3.6**

SB

P C

han

ge

(mm

Hg

)

** p** p 0.001 vs enalapril0.001 vs enalapril

**

% o

f P

atie

nts

% o

f P

atie

nts

Omapatrilat Enalapril

Target Population – Severity of Target Population – Severity of Angioedema Events, Week 24Angioedema Events, Week 24

(Diabetes, Renal Disease, Athero Disease, HF)(Diabetes, Renal Disease, Athero Disease, HF)

OCTAVE (CV137-120)

Number (%) of Patients

Omapatrilat(n = 2842)

Enalapril(n = 2807)Severity

I. No Treatment Administered or Antihistamines Only

II. Treated with Catecholamines or Steroids

III. Hospitalized but no Mechanical Airway Protection IIIa. No Airway Compromise

IIIb. With Airway Compromise

IV. Mechanical Airway Protection or Death from Airway Compromise

Total

28 (0.99%) 14 (0.50%)

15 (0.53%) 2 (0.07%)

2 (0.07%) 1 (0.04%)

2 1 0 0

0 (0%) 0 (0%)

45 (1.58%) 17 (0.61%)

CV137-073

-10.7 -10.9

-3.1

0.6

-12

-10

-8

-6

-4

-2

0

2

AS

BP

Ch

ang

e (m

mH

g)

ACE-I Monotherapy

(n = 171)

ACE-ICombination

(n = 75)

Change in 24-Hour Average AmbulatoryChange in 24-Hour Average AmbulatorySystolic BP in Patients UncontrolledSystolic BP in Patients Uncontrolled

with ACE-Inhibitor Regimens at Baselinewith ACE-Inhibitor Regimens at Baseline

Omapatrilat 80 mg Lisinopril 40 mg

-7.6** -11.5**

Week 4 Maintenance* *p 0.001 vs. lisinopril

Patients uncontrolled with

a regimen not including an ACE-I

Omapatrilat provides consistent benefit in BP Omapatrilat provides consistent benefit in BP reduction over enalapril in each of these difficultreduction over enalapril in each of these difficultto control populations.to control populations.

Difficult to Control PatientsDifficult to Control Patients

Untreated patients with severe

hypertension

Patients uncontrolled with

a regimen including an ACE-I

Difficult to Control Patients

BP Control in Uncontrolled Patients at Sites with BP Control in Uncontrolled Patients at Sites with Highest Adjunct Use (64.0% - 100%) at Week 24Highest Adjunct Use (64.0% - 100%) at Week 24

OCTAVE (CV137-120)

Change in SBP

(mmHg)BP Control

n / N (%)

Omapatrilat (n = 967)

Enalapril (n = 966)

544 / 907 (60.0%)

466 / 903 (51.6%)

Difference

-

19.1

-

15.7

-3.4

Omapatrilat Educational ProgramOmapatrilat Educational Program

MD EducationMD Education

Initial MD-Patient ConsultationInitial MD-Patient ConsultationPatient BrochurePatient Brochure

Rx GivenRx Given

Mandatory Mandatory Counseling ServiceCounseling Service

Retail PharmacistRetail PharmacistEducationEducation

Retail Pharmacist Validation Retail Pharmacist Validation of Counseling and Delivery of Counseling and Delivery

of Patient Educationof Patient EducationMedication Dispensed in Medication Dispensed in Unit-of-Use Packaging Unit-of-Use Packaging

Message with PPIMessage with PPI

Follow-up MD Follow-up MD Patient ConsultationPatient Consultation

Rx GivenRx Given

Counseling PharmacistCounseling PharmacistEducationEducation